Abstract
Caveolin-1 (Cav-1) is overexpressed in aggressive and metastatic prostate cancer (PCa) and induces PCa cell proliferation. Androgens mediate lipid synthesis through acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FASN). We investigated the Cav-1-mediated lipid synthesis in the development of castration resistance, and identified novel therapeutic opportunities. Using the PBCre+;Ptenloxp/loxp;PBCav-1+ mouse model we found that Cav-1 induction increased cancer incidence and growth, and ACC1-FASN expression in intact and castrated mice. We demonstrated that Cav-1 regulated ACC1 and FASN expression in an AR-independent way and increased palmitate synthesis using western blot analysis, qRT-PCR and mass spectrometry in vitro. By using FASN siRNA and C-75, we found that FASN inhibition was more effective in Cav-1-overexpressing cells. This inhibition was abrogated by ACC1si RNA, revealing the role of malonyl-CoA, an ACC1 product, as a mediator of cytotoxicity. Cav-1 was associated with ACC1 in human tumors and ACC1, FASN, and Cav-1 expression were increased in metastatic PCa compared to primary tumors and normal prostate epithelium. Palmitoleate and oleate levels were higher in BMA from patients with metastatic PCa who responded poorly to abiraterone acetate. Our findings suggest that Cav-1 promotes hormone resistance through the upregulation of ACC1-FASN and lipid synthesis under androgen deprivation, suggesting that FASN inhibition could be used to treat PCa that demonstrates Cav-1 overexpression.
Highlights
Metastatic prostate cancer (PCa) remains an incurable disease; it inexorably progresses under androgen deprivation, leading to a lethal state known as metastatic castration-resistant PCa [1]
Downregulation of Cav-1 in PC-3M cells led to decreased palmitate levels (P=0.01) (Figure 2J). These results suggest that Cav-1 induced acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FASN) expression, activating fatty acid synthesis in PCa cells under androgen-depleted conditions, through an Androgen receptor (AR)-independent mechanism, acting mainly at the transcriptional level
We showed that Cav-1 induction promoted ACC1 and FASN expression in AR+ PCa cells and increased AR phosphorylation and protein levels
Summary
Metastatic prostate cancer (PCa) remains an incurable disease; it inexorably progresses under androgen deprivation, leading to a lethal state known as metastatic castration-resistant PCa (mCRPC) [1]. Androgen receptor (AR) remains active during the development of CRPC, indicating that its downstream signaling promotes survival and growth in androgendepleted conditions. Moon et al found that androgens enhance de novo lipid synthesis in PCa cells [5]. These results, supported by those of other reports [6, 7], suggest that one of the pathways mediating the growth effects of AR is lipid synthesis. Inhibitors of FASN and ACC1, such as C-75 and TOFA, respectively, induce apoptosis and growth arrest in PCa cells [8, 9]
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